4.5 Article

Methylated ccfDNA from plasma biomarkers of Alzheimer's disease using targeted bisulfite sequencing

Journal

EPIGENOMICS
Volume 14, Issue 8, Pages 451-468

Publisher

FUTURE MEDICINE LTD
DOI: 10.2217/epi-2021-0491

Keywords

Alzheimer's disease; bisulfite sequencing; DNA methylation; methylated ccfDNA; noninvasive biomarkers; plasma

Funding

  1. Centre National de Recherche en Genomique Humaine
  2. Le Laboratoire d'Excellence en Genomique Medicale [ANR-10-LABX-0013]
  3. France Genomique [ANR-10-INBS-0009]
  4. European Union's Horizon 2020 research and innovation programme (European Advanced infraStructure for Innovative Genomics) [824110]

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This study developed a targeted sequencing protocol to identify potential noninvasive biomarkers of Alzheimer's disease (AD) based on methylated ccfDNA. The authors identified methylated CpGs that were consistent with previous AD studies, as well as potential novel sites. These findings suggest that methylated ccfDNA could be a useful noninvasive biomarker for AD.
Aim: Noninvasive biomarkers such as methylated ccfDNA from plasma could help to support the diagnosis of Alzheimer's disease (AD). Methods: A targeted sequencing protocol was developed to identify candidate biomarkers of AD in methylated ccfDNA extracted from plasma. Results: The authors identified differentially methylated CpGs, regions of which were the same as those identified in previous AD studies. Specifically, a differentially methylated CpG of the LHX2 gene previously identified in a plasma study of AD was replicated in the study. The MBP and DUSP22 regions have been identified in other brain studies of AD and in the authors' study. Conclusion: Although these biomarkers must be validated in other cohorts, methylated ccfDNA could be a relevant noninvasive biomarker in AD. Plain language summary Currently, the diagnosis of Alzheimer's disease (AD) is based on symptoms and medical imaging, and definitive clinical diagnosis is only possible postmortem. The identification of noninvasive biomarkers such as methylated ccfDNA is crucial for the diagnosis, prognosis and monitoring of AD. However, the analysis of ccfDNA from plasma is a challenge because it is highly fragmented and present in low amounts and originates from various tissues. The authors developed a targeted sequencing protocol using genes previously reported in AD literature (brain, blood and plasma) to identify potential noninvasive biomarkers in plasma. The authors identified positions identical to those in the literature as well as potential novel sites located in the promoter, exon and intron regions of these genes. Although these results must be validated in a large cohort, methylated ccfDNA could be a useful noninvasive biomarker for AD.

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